5-143343808-G-C

Variant names:

• chr5-143343808-G-C
• rs2918418
• NM_000176.3:c.1185-29640C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000176.3(NR3C1):​c.1185-29640C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,154 control chromosomes in the GnomAD database, including 1,871 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (1871 hom., cov: 32)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.426
• Publications: 16 publications found

Genes affected

NR3C1 (HGNC:7978): (nuclear receptor subfamily 3 group C member 1) This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175). [provided by RefSeq, Feb 2011]

NR3C1 Gene-Disease associations (from GenCC):

• glucocorticoid resistance

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000176.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.1185-29640C>G		intron	N/A	NP_000167.1
	NR3C1	NM_001024094.2		c.1185-29640C>G		intron	N/A	NP_001019265.1
	NR3C1	NM_001364183.2		c.1185-29640C>G		intron	N/A	NP_001351112.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.1185-29640C>G		intron	N/A	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.1185-29640C>G		intron	N/A	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.1185-29640C>G		intron	N/A	ENSP00000422518.1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22593 AN: 152036 Hom.: 1867 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.0718

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.119

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.149 AC: 22629 AN: 152154 Hom.: 1871 Cov.: 32 AF XY: 0.147 AC XY: 10930 AN XY: 74384

African (AFR) AF: 0.177 AC: 7353 AN: 41504

American (AMR) AF: 0.0818 AC: 1251 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 215 AN: 3470

East Asian (EAS) AF: 0.0718 AC: 372 AN: 5180

South Asian (SAS) AF: 0.0329 AC: 159 AN: 4826

European-Finnish (FIN) AF: 0.206 AC: 2177 AN: 10576

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10626 AN: 67986

Other (OTH) AF: 0.118 AC: 249 AN: 2112

Alfa AF: 0.0892 Hom.: 109

Bravo AF: 0.141

Asia WGS AF: 0.0730 AC: 254 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.6
DANN	Benign	0.59
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2918418; hg19: chr5-142723373;